Process for producing medicaments which comprise HMG CoA reductase inhibitors

ABSTRACT

The invention relates to a process for producing medicaments which comprise HMG CoA reductase inhibitors in the form of their salts, characterized in that the corresponding precursors of the actual active compounds are converted with bases, which contain alkali metal or alkaline earth metal ions, in a solvent, into the active compound, and the resulting active compound-containing solution is processed into the desired administration form.

[0001] The invention relates to a process for producing medicamentswhich comprise HMG CoA reductase inhibitors and which are, inparticular, in the form of granules, tablets and pellets.

[0002] It is known that HMG CoA reductase inhibitors are employed asactive compounds in medicaments for treating hyperlipoproteinaemia andarteriosclerosis. Most of these active compounds are derived from thestatin group, having the following formula

[0003] in which

[0004] R represents an organic radical,

[0005] X represents a group —CH₂—CH₂— or —CH═CH—; in particular in the(E) form, and

[0006] M represents a physiologically acceptable cation, for examplefrom the alkali metal cation group, preferably sodium or potassium, andalso represents an ammonium ion.

[0007] It is also known that most active compounds of the statin groupare used in the form of their salts. For this, these active compoundsare usually first of all prepared, in aqueous solution, from thecorresponding esters or acids, as precursors, by treating with bases,and this solution is then lyophilized in order to obtain the actualactive compound (EP 547 000).

[0008] By its nature, this process is very time-consuming andcost-intensive and requires, inter alia, a substantial input in terms ofprocess monitoring, control and optimization. In addition to this, alyophilization product is very difficult to handle since it exhibitsvery strong hygroscopic properties. This can result in substantialproblems in storage and production (e.g. inaccuracy in weighing, andvariations in drug content in the tablets due to moisture uptake in thegranular state) despite careful adherence to climatically favourableconditions (low atmospheric humidity) or despite using specialmoisture-tight packing materials.

[0009] A process has now been found for producing medicaments whichcomprise HMG CoA reductase inhibitors of the statin group having thegeneral formula (I)

[0010] in which

[0011] R represents an organic radical,

[0012] X represents a group —CH₂—CH₂— or —CH═CH—, and

[0013] M represents a pharmacologically acceptable cation,

[0014] characterized in that the actual active compound is first of allprepared, in aqueous solution/suspension, from the corresponding activecompound precursor by treating the latter with an aqueous base, and thisactive compound-containing solution/suspension is then either directlysprayed onto excipients, and dried in parallel with this, or granulatedafter mixing the active compound-containing solution/suspension withsuitable binders and excipients, and then dried.

[0015] The novel process consequently describes the production ofmedicaments without the active compound being isolated in its solid formor as a pure substance but, instead, being directly subjected to furtherprocessing as a solution.

[0016] This considerably simplifies the entire production process,particularly because the problematical and expensive lyophilization stepfor isolating the active compound is dispensed with. This also bringsabout a substantial improvement in the manageability and productivereliability of the medicinal preparation.

[0017] In general, those bases which contain alkali metal and alkalineearth metal ions are used as bases. Preference is given to hydroxides,carbonates or hydrogen carbonates which contain alkali metal or alkalineearth metal ions, such as sodium, potassium, lithium, beryllium, calciumor magnesium ions. Particular preference is given to using sodiumhydroxide or potassium hydroxide, depending on whether the actual activecompound is a sodium salt or a potassium salt.

[0018] The quantity of base is at least an equimolar quantity inrelation to the quantity of active compound precursor employed.

[0019] In this context, precursors are understood as meaning thecorresponding acids or esters of the formula (II)

[0020] or the corresponding lactones of the formula (III)

[0021] in which

[0022] R represents an organic radical,

[0023] X represents a group of the formula —CH₂—CH₂— or —CH═CH—, and

[0024] R¹ represents a C₁-C₄-alkyl group or hydrogen.

[0025] Preference is given to employing the lactones of the formula(III) as precursors, with the actual active compounds being prepared bycleaving the lactone ring with the base directly in the solution.

[0026] Cerivastatin lactone, which is converted, in solution, withsodium hydroxide into the active compound cerivastatin, is particularlypreferably suitable.

[0027] The novel process is suitable for producing solid and liquid, inparticular solid medicinal forms, such as active compound-containingpowders, granules, tablets or pellets. In this connection, it ispossible to compress the powders, granules or pellets into tablets or tofill them into capsules.

[0028] As binding agents for the granulation, all the customarypharmaceutically acceptable binding agents can be used, e.g.polyvinylpyrrolidones, gelatin and starch and cellulose derivatives(natural or synthetic). Polyvinylpyrrolidones, e.g. polyvinylpyrrolidone25, are preferred.

[0029] All the customary pharmaceutical excipients can be used asadditional auxiliary substances, thus cellulose derivatives (e.g.microcrystalline cellulose), sugars (e.g. lactose), sugar alcohols (e.g.mannitol or sorbitol) and inorganic fillers (e.g. calcium phosphates)can, for example, be used as fillers, and use can also be made of allthe other excipients which are required for producing medicinalformulations having the desired properties, e.g. lubricants (e.g.magnesium stearate), e.g. disintegrants (e.g. crosslinkedpolyvinylpyrrolidone or sodium carboxymethyl cellulose), e.g. wettingagents (e.g. sodium lauryl sulphate), e.g. stabilizers, e.g. fragrancesand e.g. dye pigments.

[0030] Lactose, mannitol and microcrystalline cellulose are preferablyused as fillers.

[0031] he proportion of binding agent in the total mixture is preferablyfrom 0 to 20%. The proportion of fillers and auxiliary substances in thetotal mixture is preferably from 70 to 99%.

[0032] The drying temperature is generally from 40 to 120° C.,preferably from 60 to 100° C.

[0033] The novel process is particularly suitable for active compoundsof the formula (I) in which the substituent R denotes an optionallysubstituted pyrimidine, indole, indolizine, pyrrolopyridine, quinoline,dihydroquinoline, pyrazolopyridine, pyridazine, imidazole,pyrroloisoquinoline, pyridine, pyrrole or tetrazole radical.

[0034] The novel process is particularly suitable for the followingactive compounds of the formula (I):

[0035] pravastatin,

[0036]3R,5S-(E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-dimethylaminopyrimidine-5-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0037]erythro-(±)-(E)-7-[3-(4-fluorophenyl)-spiro[cyclopentane-1,1¢-1H-inden]-2¢-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0038]3R,5S-(E)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-indolizin-3-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0039]3R,5S-(E)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,5-dihydroxy-8-heptenoicacid, sodium salt;

[0040]3R,5S-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-quinolin-3-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0041]3R,5S-(E)-7-[1-(4-fluorophenyl)-3-(1-methylethyl)-4-oxo-1,4-dihydroquinolin-2-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0042]3R,5S-(E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0043]3R,5S-(E)-7-(3-(1-methylethyl)-5,6-diphenyl-pyridazin-4-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0044]3R-5S-(E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-phenyl-pyrimidin-5-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0045]3R,5S-(E)-7-[4-(4-fluorophenyl)-1-(1-methylethyl)-3-phenyl-2-oxo-2,3-dihydroimidazol-5-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0046] 3R,5S-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-1-oxo-1,2-dihydro-quinolin-3-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0047]erythro-(±)-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-quinolin-3-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0048]erythro-(±)-(E)-7-[1-(4-fluorophenyl)-3-(1-methylethyl)-pyrrolo-[2,1-a]isoquinolin-2-yl]1-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0049]erythro-(±)-(E)-7-[4-cyclopropyl-6-(4-fluorophenyl)-2-(4-methoxyphenyl)pyrimidin-5-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0050]3R,5S-(E)-7-[4-(4-fluorophenyl)-2,6-dimethylpyrimidin-5-yl]-3,5-dihydroxy-8-heptenoicacid, sodium salt;

[0051]3R,5S-(E)-7-[4-(4-fluorophenyl)-6-methyl-2-phenyl-pyrimidin-5-yl]-3,5-dihydroxy-8-heptenoicacid, sodium salt;

[0052]3R,5S-(E)-7-[4-(3,5-dimethylphenyl)-6-methyl-2-phenyl-pyrimidin-5-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0053]erythro-(±)-(E)-7-[3,4-bis(4-fluorophenyl)-6-(1-methylethyl)-pyridazin-5-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0054]erythro-(±)-(E)-7-[1-(4-fluorophenyl)-3-(1-methylethyl)-5-phenyl-1H-pyrrol-2-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0055]erythro-(±)-(E)-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid, sodium salt;

[0056] erythro-(±)-(E)-3,5-dihydroxy-9,9-diphenyl-6,8-heptenoic acid,sodium salt;

[0057]erythro-(±)-(E)-7-[4-(4-fluorophenyl)-1,2-bis(1-methylethyl)-3-phenylpyrrol-2-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0058]3R,5S-(E)-7-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0059]3R,5S-(E)-7-[4-(4-fluorophenyl)-2,6-bis(1-methylethyl)-5-methoxymethyl-pyuidin-3-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt; (cerivastatin)

[0060]erythro-(±)-(E)-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-pyridin-3-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0061]erythro-(±)-(E)-[2-(4-fluorophenyl)-4,4,6,6-tetramethyl-cyclohexen-1-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt;

[0062]erythro-(±)-(E)-7-[4-(4-fluorophenyl)-2-cyclopropyl-quinolin-3-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt; and

[0063]erythro-(±)-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-quinolin-3-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt.

[0064] The novel process is particularly suitable for3R,5S-(E)-7-[4-(4-fluorophenyl)-2,6-bis(1-methylethyl)-5-methoxymethyl-pyridin-3-yl]-3,5-dihydroxy-6-heptenoicacid, sodium salt.

[0065] In addition, the described process is particularly suitable whenthe active compound is only being employed in very small quantities,e.g. less than 5%, preferably less than 1% (proportion by weight in thefinal formulation). By processing the solution or suspension of activecompound into the granulation liquid and then coating the carrier,medicinal preparations can be produced in which the distribution of theactive compound is exceptionally uniform. The well known problems whicharise in association with the conventional (dry) mixing of componentswhich are present in a total mixture in very different proportions arethereby avoided in a simple manner.

EXAMPLES Example 1

[0066] A defined quantity of the active compound precursor cerivastatinpyridine lactone is initially introduced into a suitable vessel. Thequantity of sodium hydroxide which is required for the quantitativeconversion to cerivastatin, which quantity is calculated as a molarratio between cerivastatin pyridine lactone and sodium hydroxide andwhich is in the form of an aqueous solution, e.g. 2.5% (w/w), and also afurther calculated excess of water, e.g. 6.6 times the weight ofcerivastatin pyridine lactone taken, are combined and added to thesolid. The mixture is maintained under suitable conditions for a definedtime, during which the precursor is converted into the active compoundcerivastatin. The completeness of the conversion is checked.

[0067] After the transformation has come to an end, the mixture isfiltered and polyvinyl-pyrrolidone 25 and water are then added. Thefollowing composition may be mentioned by way of example (values in [mg]in relation to the final formulation): Cerivastatin 0.1Polyvinylpyrrolidone 25 1.8 Water q.s.

[0068] The resulting granulation liquid is applied directly to asuitable carrier material, e.g. mannitol, a procedure which can beperformed, in accordance with the current state of the art, either as amixer granulation, e.g. with the aid of a high shear mixer, or as afluidized bed granulation (value in [mg] in relation to the finalformulation): Mannitol 83.95

[0069] After drying, the batch is sieved and mixed.

[0070] The resulting granules can, for example, also be mixed, after thesieving, in the added presence of suitable lubricants (e.g. magnesiumstearate) and disintegrants (e.g. crosslinked polyvinylpyrrolidone),then processed into tablets (weight, 90 mg, diameter, 6 mm) andsubsequently lacquered (protecting the active compound against light).

Example 2

[0071] Like Example 1, except that the liquid is not granulated on apulverulent carrier and is instead absorbed onto pellets in suitableapparatus, for example fluidized bed equipment fitted with a Wursterinsert.

Example 3

[0072] Like Example 1, except that the powder vehicle is rounded offinto active compound-containing pellets in suitable apparatus, forexample fluidized bed units, rotary granulators or similar equipment.

Example 4

[0073] Like Example 1,except that the liquid is absorbed onto thepulverulent support material in powder coaters, with activecompound-coated powders being produced.

Example 5

[0074] Like Examples 1 to 4, except that the active compound-coatedpowder, the granules or the pellets are filled into premade capsules,which are for example composed of hard gelatine or other suitablematerials.

Example 6

[0075] Like Example 1, except that the concentration of the activecompound per dose unit is decreased to 0.01 mg or increased to 5.0 mg.

Example 7

[0076] Like Example 1, except that a stabilizer, e.g. sodium hydroxide,is added to the granulation liquid.

Example 8

[0077] Like Example 1, except that the stabilizer, e.g. sodiumcarbonate, is added to the support material.

Example 9

[0078] For a liquid formulation (aqueous) with the option of, ifnecessary, back-titrating (adjusting, since alkaline after hydrolysis)the pH.

1. Process for producing medicaments which comprise HMG CoA reductaseinhibitors of the stating group having the general formula I

in which R represents an organic radical, X represents a group —CH₂—CH₂—or —CH═CH—, and M represents a pharmacologically acceptable cation,

characterized in that the actual active compound is prepared in aqueoussolution/suspension by treating a corresponding active compoundprecursor with an aqueous base, and this active compound-containingsolution/suspension is then either directly sprayed onto neutralexcipients, without isolating the active compound as a solid substance,and dried in parallel with this, or, after mixing the activecompound-containing solution with suitable binders, is then granulatedwith excipients and subsequently dried.
 2. Process according to claim 1,characterized in that the acids or esters

or the corresponding lactones of the formula (III)

in which R represents an organic radical, X represents a group of theformula —CH₂—CH₂— or —CH═CH—, and R¹ represents a C₁-C₄-alkyl group orhydrogen, are employed as precursors.
 3. Process according to claims 1and 2, characterized in that sodium hydroxide or potassium hydroxide isemployed as base.
 4. Process according to claims 1 to 3, characterizedin that polyvinylpyrrolidone, gelatin or starch and cellulosederivatives is/are employed as binders.
 5. Process according to claims 1to 4, characterized in that cellulose derivatives, sugars, sugaralcohols or inorganic fillers are employed as excipients.
 6. Processaccording to claims 1 to 5, characterized in that mannitol or sorbitolis employed as excipients.
 7. Process according to claims 1 to 6,characterized in that the proportion of binder in the total mixture is0-20%.
 8. Process according to claims 1 to 7, characterized in that theproportion of fillers and excipients in the total mixture is 70-99%. 9.Process according to claims 1 to 8, characterized in that at least anequimolar quantity of base, calculated in relation to the activecompound precursor, is employed.
 10. Process according to claims 1 to 9,characterized in that the quantity of active compound is less than 5% ofthe total quantity of the final medicinal form.